Severe sepsis is a systemic response to infection that culminates in acute organ failure. Preclinical models of sepsis demonstrate that a disturbed microvasculature characterized by hyporesponsive vessels and heterogeneous flow contributes to organ failure. However, translation of these findings into successful human therapies is impaired by discrepancies between animal models and human sepsis. Novel microvascular imaging provides new opportunities to study potential therapeutic targets of resuscitation in human sepsis. The renin- angiotensin system (RAS) and arginine vasopressin (AVP) system represent two response systems that undergo changes with microvascular implications in human sepsis. There are significant interactions between these systems, and both can be manipulated therapeutically. Thus both RAS and AVP appear to be important targets for resuscitation. We hypothesize that vasoconstrictor activity contributes to heterogeneous blood flow and impaired responses to ischemia in the microvasculature that culminate in organ failure and death in human sepsis. To investigate this hypothesis we have developed three specific aims. 1) Determine if impaired microvascular responses to ischemia are related to heterogeneous microvascular flow and mortality in human sepsis. We will use Near Infrared Spectroscopy (NIRS) to measure microvascular responses to ischemia, and strengthen our findings with sublingual capillary analysis. We will therefore determine microvascular function in diverse tissues in a study powered to determine if these measures are associated with mortality. We will determine which vasoconstrictors are most closely related to microvascular changes. 2) Determine the effects of AVP infusions upon RAS activation and microvascular function during human sepsis. Patients will receive either AVP or saline, and we will compare microvascular function and RAS activation. We will determine if induced changes in microvascular flow and responsiveness are consistent with changes in RAS activation. 3) Investigate RAS as a potential target of microvascular resuscitation in human sepsis. We will inhibit RAS in the regional microcirculation of septic subjects, thereby testing if RAS contributes to impaired microvascular responses to ischemia. Through collaboration between an intensivist- investigator and a physician-scientist with expertise in clinical studies of vascular regulation, we propose studies that will be pertinent to patient outcomes and elucidate important mechanisms that contribute to microvascular dysfunction in human sepsis. PUBLIC HEALTH RELEVANCE: Narrative Severe sepsis is a systemic response to infection that afflicts 750,000 Americans annually, and is associated with 30% mortality. Abnormal microvascular function may be a key factor that contributes to these deaths. We propose a series of studies that will demonstrate the physiologic meanings of impaired microvascular regulation, and also will identify potential mechanisms that lead to these impairments.